Clinical and experimental evidences show that a eustachian tube obstruction is causally associated with pathophysiologic changes in the middle ear including the development of significant underpressures, and if prolonged, otitis media with effusion. The mechanism most often invoked to explain this relationship is the ex vacuo theory which consists of three causally related components; 1) the unabated absorption of ME gases, 2) a resultant ME underpressure (400-600 mmH2O) and 3) a transudation of fluid from the ME mucosa to the ME space. However, a comprehensive evaluation of the assumptions inherent in this theory has not been undertaken and a generalized predictive model of systems response is lacking. Some recent data are incompatible with this theory suggesting that our understanding of the pressure regulation of the middle ear is incomplete. The experiments outlined in this proposal extend our previous work on pathophysiology from a concentration on the role of eustachian tube dysfunction in initiating/prolonging otitis media to the direct consequences of that dysfunction, i.e. altered mucosal gas and fluid exchange. Specifically, the study will test the validity of the component assumptions of the classical ex vacuo theory using a well characterized monkey system. Models of gas exchange across the middle ear mucosa will be constructed and the changes in model parameters associated with disease conditions will be documented. Also, the role of middle ear underpressures in the development of effusion will be investigated. These models will be used to predict the results of experiments conducted prospectively and in the evaluations of pre-existing data sets. Confirmation of the primary hypothesis, i.e. altered N2 exchange during mucosal inflammation will explain a variety of past observations and may lead to the development of a non-invasive test for mucosal health. The latter would be useful in determining when to perform tympanoplasties or at which point in time tympanotomy tubes could be removed with a minimal likelihood of disease recurrence.